Periodontal disease is one of the world's most prevalent chronic diseases. It is estimated that up to 42% of adult Americans have some sign of the disease [1]. Periodontitis is a multifactorial infection with complex and interconnected mechanisms of pathogenesis [2]. The interplay between bacteria within the sulcus and periodontal pocket and the response they elicit in the host defense mechanisms, which in turn can be modified by genetic and acquired risk factors, produces the prospects of a large number of possible permutations of how the disease might present clinically and how it might progress [3,4]. Bacteria have long been established as the etiologic agents [5]. Nearly 800 species of aerobic and anaerobic bacteria have been identified in the oral cavity [6,7]. Only a few, however, have been associated with the connective tissue dissolution, apical migration of the epithelial attachment, and alveolar bone loss that characterize the disease process [8].

In general, chronic adult periodontitis may be defined as a mixed anaerobic infection where the overgrowth of potential pathogens is influenced by local factors within the bacterial community and the impact of host defense mechanisms elaborated within the pocket. Some of the most commonly implicated micro-organisms associated with periodontal destruction are Porphyromonas gingivalis, Bacteroides forsythus, Treponema denticola, and Aggregatibacter (formerly Actinobacillus) actinomycetemcomitans [6,10,11]. This group of micro-organisms has been shown to be strongly associated with the progression of the disease as measured by clinical assessment parameters. It is now apparent that even within a given pathogenic species, only certain subsets or clonal types may be pathogenic. It is postulated that these pathogenic microorganisms produce tissue destruction through the release of virulence factors that induce the elaboration of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1B) and tumor necrosis factor-alpha (TNF-a). These agents bind to fibroblast receptor sites, inducing the secretion of prostaglandins (PGE), culminating in the release of matrix metalloproteinases (MMPs) that degrade connective tissue and cause bone resorption, producing the clinical manifestations of pocket depth, bone loss, and bleeding on probing [11].

The formation of the periodontal pocket, characteristic of periodontal disease, is the direct result of connective tissue destruction of the periodontal ligament fibers. In health, these fibers insert into the root surface at the cemento-enamel junction and apically. Dissolution of these fibers from their root surface attachment permits the apical migration of epithelial cells onto the root surface and the subsequent exposure of the root surface to bacterial colonization and the contents of the developing periodontal pocket [32]. The amount of periodontal destruction, defined in terms of connective tissue loss and root surface exposure, can thus be calculated as a clinical attachment loss (CAL) measured from the cemento-enamel junction. In areas of hyperplasia, sulcular depth may be greater than the customarily accepted norm of 1–3 mm, but until connective tissue fibers are dissolved and the root surface is exposed, periodontal disease is not present. This affects the clinician's choice of therapeutic measures to employ once a diagnosis has been made. A 7-mm sulcular depth on the distal of a second molar may be completely hyperplastic with no connective tissue dissolution present, no root exposed, and no periodontal disease present. The enamel surface may be scaled, but it is not feasible to root plane when no root is exposed to treat. Concurrent with the dissolution of connective tissue attachment on the root surface, the alveolar bone may also be resorbed.

Periodontal pocket depth measurements are made by carefully placing a periodontal probe into the sulcular area and determining the distance, in millimeters, from the height of the gingiva to where the probe comes to rest at the base of the sulcus or periodontal pocket. Where the probe ends with relation to the tooth surface and to the epithelial attachment is variable. The probe does not, in most instances, stop at the base of the sulcus, even in health, but will penetrate to some extent into the epithelial attachment. What restricts the probe from going further into the epithelial attachment is the health of the supporting, underlying connective tissue. As inflammation increases in the connective tissue, its integrity and ability to support the overlying degenerating epithelium and resist the penetration of the probe lessens and the probe penetrates to reach the connective tissue attachment at the base of the sulcus. When the probe reaches the connective tissue, the clinical sign of bleeding is produced. As there is no blood supply within epithelium, when the clinician produces bleeding upon probing, the connective tissue has been contacted. Depending upon the force used in the placement of the probe and the degree of inflammation present, the probe may penetrate into the underlying connective tissue. Thus, a patient who undergoes a periodontal pocket depth examination when the tissues are inflamed will give a pocket depth reading based on the presence of the periodontal probe within the connective tissue. With reduction in the degree of inflammation in the connective tissue and return to health of the epithelial attachment, the probe, given the same amount of force applied, will not penetrate to the previous depth but will stop somewhere within the newly formed epithelial attachment. The difference between these two levels may be as much as 2 mm. This does not mean that there is a gain of 2 mm in attachment, but rather it is a reflection of the variability of how far the probe penetrates as determined by the relative health of the underlying connective tissue [42].

Subgingival bacterial plaque behaves as a biofilm. Consisting of bacterial communities that exist in a self-produced, hydrated polymeric matrix, biofilm attaches to both living and nonliving surfaces. The bacteria that are present within the biofilm are organized into a community that is resistant to host defenses and antibiotics and may impair the diffusion of or inactivate pharmacologic agents [6,59]. In order for an agent to have an effective action on the bacteria within the biofilm, it must meet all three pharmacokinetic parameters [60]:

Subgingival bacterial plaque behaves as a biofilm. Consisting of bacterial communities that exist in a self-produced, hydrated polymeric matrix, biofilm attaches to both living and nonliving surfaces. The bacteria that are present within the biofilm are organized into a community that is resistant to host defenses and antibiotics and may impair the diffusion of or inactivate pharmacologic agents [6,59]. In order for an agent to have an effective action on the bacteria within the biofilm, it must meet all three pharmacokinetic parameters [60]:

Another factor to consider when placing antimicrobial agents within the periodontal pocket is the clearance of the area through the action of the GCF. GCF is an altered serum transudate found in the gingival sulcus and is a result of mechanical irritation or the response to the presence of micro-organisms and their products within the pocket. There is an ongoing flow of GCF when the tissue is mechanically irritated or inflamed. It has been estimated that in a 5-mm periodontal pocket, the contents of that pocket are replaced about 40 times each hour [31]. Thus, any antimicrobial agent placed subgingivally has its concentration rapidly reduced by GCF flow [31]. The estimated half-life of any pharmacologic agent placed in the periodontal pocket is about one minute. This very high rate of clearance represents a significant obstacle in producing and maintaining effective concentrations to effectively impact the bacteria within the biofilm. Because of this high rate of GCF clearance, it became evident that to prolong therapeutic duration, the use of a subgingival drug reservoir needed to be developed that could release the agent over a period of time, counteracting its continuous loss due to GCF flow.

A number of local delivery devices have been developed to provide a reservoir of the antimicrobial agent that would limit the release, providing for application over an extended period of time. The goal is to maintain a sufficient concentration of the agent in the site despite GCF clearance [61]. Local delivery devices may be categorized in two classes according to release and duration [31]:

As a result of decades of research and development, a number of products have been developed and marketed for use, including Actisite (no longer available in the United States), PerioChip, Atridox, and Arestin [65,66].

PerioChip is a bioabsorbable local delivery device comprised of 34% chlorhexidine gluconate in a cross-linked hydrolyzed gelatin matrix. Each chip is 5 mm by 4 mm by 0.035 mm and is impregnated with 2.5 mg of chlorhexidine. Chlorhexidine gluconate is a long-chain molecule with a positive charge that is attracted to the negatively charged surface of the biologic membranes of bacterial and epithelial cells. Chlorhexidine has a nonspecific mechanism of action against bacteria. It attaches to the cell walls, disrupting them and entering the cell. This disrupts the cytoplasm, which flows out of the ruptured cell resulting in bacterial death [66,68].

In vitro studies of the release of chlorhexidine from its carrier showed that 40% of the chlorhexidine was released within 24 hours, with the remainder being released in the subsequent 7 to 10 days [69,70]. The mean concentration for the seven-day period was 125 mcg/mL, in contrast to a level of 1,450 mcg/mL at four hours, a second peak of 1,900 mcg/mL at 72 hours, and 480 mcg/mL at three days. Studies have shown suppression of the pocket flora for up to 11 weeks following treatment with PerioChip [11].

PerioChip is placed in an isolated and dry field. The chips are shipped refrigerated and stored in a like manner [66]. When cool, the chip is firm, but when left at room temperature for any period of time, it softens as it absorbs moisture from the air. A softened chip is more difficult to place. For placement, the chip must be grasped with cotton forceps, with the curved end of the chip directed apically and gently placed into the periodontal pocket, to the depth of the pocket. It is reported to be self-retentive and to biodegrade over the subsequent 7- to 10-day period [66,68,69].

Atridox is a biodegradable formulation for subgingival controlled release containing 10% by weight of doxycycline hyclate and a vehicle, each in a separate plastic syringe. One syringe contains 42.5 mg of doxycycline; the other contains 450 mg of the ATRIGEL Delivery System, a flowable polymeric formulation that is a combination of 36.7% poly-DL-lactide (PLA) dissolved in 63.3% N-methyl-2-pyrrolidone (NMP). The contents of the two syringes are mixed. Upon contact with oral fluids, the product becomes less fluid and eventually solidifies, permitting controlled release of doxycycline for seven days [76].

Doxycycline is a broad-spectrum, semisynthetic tetracycline that is bacteriostatic through inhibition of bacteria protein synthesis due to disruption of transfer ribonucleic acid (RNA) and messenger RNA at ribosomal sites. In vitro testing has indicated that several of the periodontal pathogens, including P. gingivalis and Fusobacterium nucleatum, are susceptible to doxycycline at concentrations of 6 mcg/mL [76].

Several multicenter studies evaluated and compared Atridox to placebo control using the vehicle only, oral hygiene, or SRP alone [78]. Four hundred and eleven patients were evaluated in each study. Each patient demonstrated moderate-to-severe periodontitis with at least two or more quadrants, each with a minimum of four qualifying pockets of 5 mm or greater pocket depth that bled on probing. At least two of the pockets were 7 mm or greater. Treatment was provided at baseline and again at four months. Clinical parameters were recorded monthly. Patients received one of the four options in both quadrants. Note that this study evaluated the use of Atridox as a monotherapy (for which it is approved) in contrast to SRP, not in combination with SRP. These clinical trials took place over nine months and involved 19 university dental centers; the data was combined from these centers.

Arestin is a controlled-release product containing the antibiotic, minocycline hydrochloride, in a bioresorbable polymer, poly (glycolide-co-D,L-lactide) or PGLA. Minocycline is a member of the tetracycline class of antibiotics and has a broad spectrum of activity. Similar to the other members of the class, it is bacteriostatic and exerts its antibacterial effect by inhibiting protein synthesis [66]. In vitro susceptibility testing yielded results similar to other members of the class, showing activity against organisms such as P. gingivalis, Prevotella intermedia, F. nucleatum, Eikenella corrodens, and A. actinomycetemcomitans [69].

Each unit dose cartridge delivers minocycline hydrochloride equivalent to 1 mg of minocycline. The agent is provided in a bioadhesive, bioresorbable polymer (PGLA) produced in a microencapsulation process [69]. Once inserted into the periodontal pocket, these microspheres adhere to the walls of the pocket. GCF hydrolyzes the polymer, causing water-filled channels to form inside the microspheres. These areas provide for the encapsulated antibiotic to be released.

Over a two-week period, the minocycline diffuses from the microspheres as they are hydrolyzed. At day 14, a level of 340 mcg/mL has still been found in the pocket. Eventually the microspheres themselves are completely fragmented and bioresorbed [81].

Although Arestin has the clinical advantage of ease of application, one drawback is that it is a single-site placement agent providing 1 mg of antibiotic per site. This is in contrast to Atridox, which contains 42.5 mg of doxycycline and may be used for multiple sites with the same unit provided. Arestin is provided in single-use dosages with a syringe. The unit dosage is applied to the syringe, the cannula placed into the periodontal pocket, and the agent dispersed into the site. The manufacturer does not recommend any means of further retention of the product. The product does not have to be refrigerated. A requirement for application in several sites would necessitate several unit dosages [69,81].

The first subject to consider before structuring treatment protocols is the necessity for a basic change in practice philosophy. That is, the perspective for treatment of any given patient should be altered from restorative to periodontal. Typically, in a practice providing general dentistry, the perspective is for short-term benefit. General dentistry provides restorative solutions that are lasting and require follow-up that is not as critical as that required for periodontal therapy. If the practice is to institute a program of periodontal therapy, incorporating the utilization of site-specific agents, then the entire practice's attitude toward treatment should shift to the long-term [34]. This requires informing patients of the necessity for more frequent visits and the requirement for monitoring and maintenance of gains achieved through initial therapy. After patients are diagnosed with periodontal disease, the recurrence of the disease process and its multifactorial complexity requires that the patient understands that [16,38,40]:

Stage I periodontitis requires nonsurgical treatment. No post-treatment tooth loss is expected and a good prognosis is indicated going into maintenance. Stage II periodontitis requires both nonsurgical and surgical treatment. No post-treatment tooth loss is expected, and the prognosis is good going into maintenance. Stage III requires surgical and possibly regenerative treatments. A loss of up to four teeth may occur. The complexity of implant and/or restorative treatment is increased, and the patient may require multispecialty treatment. The overall prognosis is fair. Stage IV may require advanced surgical treatment and/or regenerative therapy, including augmentation treatment to facilitate implant therapy. Very complex implant and/or restorative treatment may be needed. The patient often requires multispecialty treatment. The overall prognosis for stage IV is questionable going into maintenance [39].

There are many individual circumstances that may require ongoing consideration for controlled-release antimicrobials during the course of the maintenance period. These include: inoperable sites distal to the lower second molars, furcation involvement where further surgical or definitive therapy is not possible, maxillary incisors where esthetics is a consideration, and areas showing advancing disease. It is absolutely essential that clinicians are very conscientious about monitoring the disease presence and activity through pocket depth readings and evaluations at each maintenance visit. The patient should be forewarned of the possible necessity for the utilization of localized agents when the need presents itself. It is appropriate to treat the patient immediately rather than delay another three months to see if further progression occurs [17,34]. This means that the patient must be prepared for the fee associated with periodontal maintenance procedures, which should be greater than that for a prophylaxis, and also be prepared for the additional fee of the localized therapy. If this is communicated from the initial exam through the initial therapy and at each maintenance visit, the patient is much more likely to accept and go forward with the recommended treatment.